The problems associated with cocaine abuse are multiple, complicated, and poorly understood. Studies of all aspects of cocaine abuse are needed, including neurobiological, behavioral, clinical, psychological, and societal. The long term objective of the proposed research is a better understanding of the neurobiology of cocaine so that progress may be made in the developmental stage. However, it seems clear from studies thus far that the basic neurobiology of cocaine must be understood at the synaptic level. Although the weight of the evidence thus far indicates that monoaminergic systems play an important role in the neurobiology of cocaine, knowledge of the underlying mechanisms at the membrane and molecular levels is sparse. The more immediate objective of this research is to determine the mechanisms by which cocaine alters synaptic function of the monoaminergic neurotransmitters, DA, NE, an 5-HT. These mechanisms will be studied in synaptosomes from the rat. Experiments in the absence of cocaine will be compared to experiments in which cocaine is present in incubation solutions. Concentration of cocaine will be varied between 10-7 and 10-5 molar. The specific aims are to answer the following questions: (1) What is the mechanism by which cocaine alters transmitter uptake? (a) Does cocaine affect the energy source for transmitter uptake, either by altering the role of NA in transport or by altering membrane potential (EM)? (2) Are the effects of cocaine on the kinetic constants the same as that produced by alteration in EM? (3) What is the mechanism by which cocaine alters exogenous transmitter release? (4) How do the in vitro effects of cocaine differ from single cocaine injections or daily injection for three weeks which will be examined in other studies? Accomplishment of the specific aims of the proposed research will greatly expand our knowledge of the mechanism of cocaine's effects on these neurotransmitter systems.